Convallatoxin enhance the ligand-induced mu-opioid receptor endocytosis and attenuate morphine antinociceptive tolerance in mice

Sci Rep. 2019 Feb 20;9(1):2405. doi: 10.1038/s41598-019-39555-x.


Morphine is a unique opioid analgesic that activates the mu-opioid receptor (MOR) without efficiently promoting its endocytosis that may underlie side effects. Our objective was to discover a novel enhancer of ligand-induced MOR endocytosis and determine its effects on analgesia, tolerance and dependence. We used high-throughput screening to identify convallatoxin as an enhancer of ligand-induced MOR endocytosis with high potency and efficacy. Treatment of cells with convallatoxin enhanced morphine-induced MOR endocytosis through an adaptor protein 2 (AP2)/clathrin-dependent mechanism, attenuated morphine-induced phosphorylation of MOR, and diminished desensitization of membrane hyperpolarization. Furthermore, co-treatment with chronic convallatoxin reduced morphine tolerance in animal models of acute thermal pain and chronic inflammatory pain. Acute convallatoxin administration reversed morphine tolerance and dependence in morphine-tolerant mice. These findings suggest convallatoxin are potentially therapeutic for morphine side effects and open a new avenue to study MOR trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesia / methods
  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Animals
  • Disease Models, Animal
  • Endocytosis / drug effects
  • Humans
  • Ligands
  • Mice
  • Morphine / pharmacology*
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / genetics*
  • Strophanthins / pharmacology*


  • Analgesics
  • Ligands
  • Receptors, Opioid, mu
  • Strophanthins
  • Morphine
  • convallatoxin